Cathepsin K is a kind of cysteine protease and it belongs to papain superfamily. Cathepsin K is specifically recognized in osteoclast and it has a decomposing activity against bone substrate [J. Biol. Chem., 271, 12517 (1996)], so it is expected that cathepsin K inhibitor shows an effect as a bone resorption inhibitor, against osteoporosis, bone fracture, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia, osteometastasis of carcinoma, periodontal disease, bone Paget's disease and other bone-metabolic diseases, in which pathological bone resorption is recognized.
On the other hand, PTH (also called parathyroid hormone or parathormone) is a hormone which is assumed to be produced in the chief cells of parathyroid, and it increases blood calcium concentration and is controlled by the phosphorus level.
It is known that PTH shows a stimulating effect on bone formation by intermittant administration and that it increases BMD. Since PTH has a stimulating effect on bone formation, unlike in the case of existing drugs consisting mainly of bone resorption inhibitors, PTH is expected to be a new type of a drug for osteoporosis.
Osteoporosis is classified in two types of pathologies; primary osteoporosis and secondary osteoporosis. Primary osteoporosis consists mainly of postmenopausal osteoporosis and senile osteoporosis and the like. Secondary osteoporosis consists mainly of diabetic osteoporosis and steroidal osteoporosis and the like.
Both menopausal osteoporosis and senile osteoporosis show the pathologies which is disorder of bone turnover caused by inbalance of bone resorption and bone formation. Therefore, in the treatment of osteoporosis, bone resorption inhibitors and bone formation stimulators are effective and the bone turnover balance may be improved by the combining them effectively.
Examples of bone resorption inhibitors include, bisphosphonates (salts of bisphosphonic acid, abbreviated as BP hereafter), calcium formulations, estrogen receptor modulators, androgen receptor modulator, calcitonin formulations, α-calcitonin gene-related peptide formulations, ipriflavone formulations, anabolic steroid formulations, anti-RANKL (receptor activator of NF-kappa B ligand) antibody and the like; on the other hand, examples of the bone formation stimulators include, types of PTH PTHrP (parathyroid hormone related protein), BMP (bone morphogenetic protein), prostaglandin receptor agonists (EP2 agonists, EP4 agonists and the like), CaR (calcium sensing receptors) antagonist, GSK (glycogen synthase kinase) inhibitors and the like.
Also, for the treatment and/or prevention of bone metabolic diseases, the followings are also used; vitamin D and its derivatives, vitamin K and its derivatives, strontium formulations, HMG-CoA reductase inhibitors, steroidal drugs, caspase-1 inhibitors, prostaglandin receptor antagonists, farnesoid X receptor agonists, progesterone agonists, anti TN-α antibody, anti-IL-6 antibody, female hormone formulations, antiinflammatory drugs, metalloprotease inhibitors, and the like.
Although BP, which is used for the treatment of osteoporosis, has a bone resorption inhibiting effect, it is acknowledged as a problem that it suppresses bone formation (Osteoporosis Japan, 7(2), 11-16 (1999), Bone, 23(4), 333-342 (1998)).
Since bone metabolic diseases are often chronic diseases, the treatment thereof is often carried out for a long term. Therefore, it has been considered to use several drugs in combination for the improvement of patients' compliance and the therapeutic effect.
For example, an effect on increasing bone mineral density is to be more expected by combination use of bone formation stimulators and bone resorption inhibitors, but it is clinically demonstrated that alendronate sodium hydrate (BP), one of bone resorption inhibitors, does not show an effect in combination with PTH (a bone formation stimulator) (see The New England Journal of Medicine, 349, 13, 1207-1215 (2003); The New England Journal of Medicine, 349, 13, 1216-1226 (2003)).
On the other hand, cathepsin K inhibitors are known as the drugs which have a bone resorption inhibiting effect. Cathepsin K inhibitors, unlike BP, do not inhibit simian bone formation (see Journal of Bone and Mineral Research, 16, 10, 1739-1746 (2001)).
The mechanism of bone metabolic diseases is poorly understood and it is not fully revealed which combination is best for clinically.
As to the treatment of osteoporosis, it is disclosed that a composition comprising a cathepsin K inhibitor and other agents (BP, an estrogen receptor modulator, an androgen receptor modulator, PTH, PTHrP, an osteoclast proton-ATPase inhibitor, an HMG-CoA reductase inhibitor, an αvβ3 receptor antagonist, a p38 kinase inhibitor, growth hormone, an EP2 agonist, a TNF-α inhibitor, a P2X7 receptor agonist, a matrix metalloproteinase inhibitor, a VEGF inhibitor and the like) is useful for the diseases of osteoporosis, osteoarthritis, osteometastasis of carcinoma (see WO03/039534).
On the other hand, it is disclosed that a compound of formula (W)

wherein all symbols have the same meaning as described in the specification of WO03/091202, has an inhibitory activity against cathepsin K and that it is useful for the treatment and/or prevention of bone diseases (see WO03/091202).
However, in these literatures, there is no evidence nor implication what kind of effect would be given by actually using a cathepsin K inhibitor and PTH in combination.